Cause Of Adolescent Idiopathic Scoliosis Research Articles

Body mass index in relation to truncal asymmetry of healthy adolescents, a physiopathogenetic concept in common with idiopathic scoliosis: summary of an electronic focus group debate of the IBSE.

There is no generally accepted scientific theory for the cause of adolescent idiopathic scoliosis (AIS). As part of its mission to widen understanding of scoliosis etiology, the International Federated Body on Scoliosis Etiology (IBSE).introduced the electronic focus group (EFG) as a means of increasing debate on knowledge of important topics. This has been designated as an on-line Delphi discussion. The text for this debate was written by Dr TB Grivas. It is based on published research from Athens, Greece evaluating schoolchildren age 11–17 years for the relation of body mass index (BMI) to each of truncal asymmetry (TA) and menarcheal status. Girls with relatively lower BMI were found to have a significant excess of severe TAs and significantly later menarche confirming the well-known relation of BMI to menarche. Together with other evidence linking nutritional status to skeletal growth, the observations suggest energy balance via the hypothalamus is related to trunk asymmetry. As with a recent speculative hypothesis for the pathogenesis of AIS in girls, Grivas et al. suggest that the severe TAs involve a genetically-determined selectively increased sensitivity (up-regulation) of the hypothalamus to circulating leptin with asymmetry as an adverse response to stress (hormesis). The TA is expressed bilaterally via the sympathetic nervous system to produce left-right asymmetry in ribs and/or vertebrae leading to severe TAs when beyond the capacity of postural mechanisms of the somatic nervous system to control the shape distortion in the trunk. This EFG discusses the findings and interpretations of the paper by Grivas and colleagues as research at the borderland between the genesis of TA (physiogenesis) and AIS (pathogenesis). It is suggested that TAs, here regarded in common with AIS, result from the combination of secondary sexual development affecting body composition, adolescent skeletal growth velocity, and an asymmetry process. The possible involvement of epigenetic factors is not considered.

Return to Athletic Activity After Posterior Spinal Fusion for Adolescent Idiopathic Scoliosis

The cause of adolescent idiopathic scoliosis (AIS) is unknown and is currently believed to be multifactorial. AIS is a largely asymptomatic condition and many adolescents with AIS are involved with organized athletics and physical activity. To date, no data exist indicating predictors of return to physical activity after posterior spinal fusion for AIS. In this cohort study, adolescents who underwent posterior spinal fusion for AIS were evaluated to determine what clinical, surgical, and demographic variables predicted rate of return play in organized athletics. Forty-two athletically active adolescents who underwent posterior spinal fusion for AIS at a single tertiary care academic orthopaedic institution by a single surgeon were analyzed for clinical, surgical, and demographic predictors of return to presurgical activity levels. Data were collected by chart review, patient interview, and completion of postoperative SRS-22 outcomes score. At an average of 5.5 years follow-up, 25 patients (59.5%) had returned to sports at an equal or higher level of physical activity. Three variables were independently associated with return to athletic activity postoperatively. The relationship between distal level of fusion and rate of return to play demonstrated a statistically significant stepwise decline from T11 to L4. Lenke classification and final SRS-22 score were also predictive of return to activity. No complications related to return to play were reported. In this retrospective cohort study, distal level of fusion, Lenke classification, and postoperative SRS-22 score were each independent predictors of rate of return to preoperative level of athletic activity after posterior spinal fusion for AIS. Prognostic Level II: retrospective Study.

Reviewer’s comment concerning ‘‘Abnormal activation of the motor cortical network in idiopathic scoliosis demonstrated by functional MRI’’ (doi:10.1007/s00586-011-1776-8) by J. Domenech et al.

Adolescent idiopathic scoliosis (AIS) is a multifactorial disorder with more questions than answers when it comes to aetiopathogenesis. Research has focussed on six major areas: genetic factors, central nervous system (CNS) abnormalities, hormones/metabolic dysfunction, skeletal growth abnormalities, biomechanical factors and environmental/life style factors [9]. Abnormalities in the CNS have long been implicated in the aetiology of AIS. Lowe et al. [6] have suggested a defect of central control or processing by the CNS that affects the growing spine, with most studies pointing to the pontine and hindbrain regions as the most likely sites of the primary pathology. Subsequent research into CNS abnormalities maybe conveniently divided into two major groups: neuroanatomical studies and neurophysiological studies. Neuroanatomical studies have demonstrated subgroups of AIS subjects with hindbrain abnormalities including cervicothoracic syrinx [5] and low lying cerebellar tonsils with or without abnormal cerebrospinal fluid dynamics [2]. Other workers have reported abnormalities in the midbrain, pons and medulla, and the vestibular system [4]. Shi et al. [7] compared volume-based morphometry of brain magnetic resonance images in AIS subjects and control subjects, detecting the differences in regional brain volumes, white matter in corpus callosum and internal capsule, and subsequently in vestibular system morphology [8]. Neurophysiological studies in AIS subjects have demonstrated a plethora of abnormalities in postural balance, somatosensory function equilibrium, proprioceptive function, oculovestibular function, electromyography, somatosensory evoked potentials, transmagnetic stimulation [9] and asymmetric motor cortex hyperexcitability [3]. The authors further developed this theme with a novel study using functional magnetic resonance imaging (fMRI) to explore cortical activation following a simple motor task in ten subjects with AIS and ten healthy age-matched controls. Compared to the controls, the AIS patients demonstrated increased activity in the contralateral supplementary motor area while performing the motor task. The authors state that these findings support the hypothesis that a sensorimotor integration disorder underlies the pathogenesis of AIS. Whilst the ‘abnormal pattern of brain activation’ in the AIS subjects is indeed an interesting observation, a causal relationship has not been proven; e.g. the scoliosis itself may in some way lead to the secondary changes observed within the brain. At best we can say that the brain of the AIS subjects is behaving ‘differently’ to that of the control subjects. The study numbers are understandably small and essentially constitute a pilot-study. The ten AIS subjects consisted of eight females and two males, eight right-handed and two left-handed subjects. The curves varied in magnitude (Cobb angle 27°–55°), curve progression (3 of 10 subjects were reported to have rapid progression) and type (6 right thoracic, 2 thoracolumbar, 1 left thoracic and 1 lumbar) thereby representing a broad spectrum of pathology. It is difficult to understand how a seemingly homogenous alteration in the activity of the contralateral supplementary motor area can produce such a heterogeneous pattern of curves that behave so differently, unless other factors are at work. We know that AIS is a multifactorial disorder. To unravel this puzzle one would need to perform a much larger study with stratification into female and male subjects, left- and right-handed individuals, low and high magnitude curves, non-progressive and rapidly progressive curves, similar curve types and see if the observations were repeatable across this larger sample. This study is provocative in that it suggests that a sensorimotor integration disorder is the cause of AIS. It certainly throws another piece of the jigsaw into an already vastly complex puzzle. However current knowledge remains fragmented; we are still not clear if the plethora of observations reported in AIS subjects are primary or secondary effects. Detailed prospective examinations of AIS subjects in tandem with serial MRI studies would allow one to ascertain whether, for example, the observed changes in the brain are linked with the cause or merely an effect of the AIS. Current treatment of AIS is aimed at preventing curve progression and improving cosmesis, that is the effect of AIS [1]. A true paradigm shift in the way we examine the aetiopathogenesis of AIS is required, if we wish to treat the cause of this condition, a prize truly worth the effort.

The role of melatonin in the pathogenesis of adolescent idiopathic scoliosis (AIS)

The cause of adolescent idiopathic scoliosis (AIS) in humans remains obscure and probably multifactorial. At present, there is no proven method or test available to identify children or adolescent at risk of developing AIS or identify which of the affected individuals are at risk of progression. Reported associations are linked in pathogenesis rather than etiologic factors. Melatonin may play a role in the pathogenesis of scoliosis (neuroendocrine hypothesis), but at present, the data available cannot clearly show the role of melatonin in producing scoliosis in humans. The data regarding human melatonin levels are mixed at best, and the melatonin deficiency as a causative factor in the etiology of scoliosis cannot be supported. It will be an important issue of future research to investigate the role of melatonin in human biology, the clinical efficacy, and safety of melatonin under different pathological situations. Research is needed to better define the role of all factors in AIS development.

Pinealectomy in the chicken: a good model of scoliosis?

The phenomenon of spinal deformity in the pinealectomized chicken has led researchers to postulate a disturbance of melatonin activity as a potential cause of adolescent idiopathic scoliosis (AIS). More recently, structural differences between curves seen in this model and those seen in scoliosis have been highlighted suggesting the deformities observed are not as similar as first thought. We examined melatonin levels, and the radiological and histological characteristics of scoliosis after pinealectomy in chickens. They underwent pinealectomy (P) at 2 days of age, sham surgery (S) or served as controls (C). Mean melatonin levels were 32.9 pmol/L (P), 175 pmol/L (S) and 227.3 pmol/L (C). Scoliosis developed in 75% of chickens after pinealectomy and 38% after a sham procedure. Nineteen percent of unoperated controls also developed scoliosis. A lower melatonin level was associated with the development of scoliosis (p < or = 0.001), but exceptions were seen with levels up to 265 pmol/L observed in one case. Most of the curves occurring spontaneously and after sham surgery and almost half after pinealectomy were short angular curves: distinct from those resembling idiopathic scoliosis. These occur over one or two segments and are characterized by marked apical wedging, frequently associated with subluxation or dislocation. The intervertebral joint in the chicken is more like a synovial joint histologically than an intervertebral disc. This study highlights important differences between the chicken and the human, and between their respective spinal deformities. Caution is advised when drawing conclusions regarding the pathogenesis of AIS from this model.

Etiologic theories of idiopathic scoliosis. Somatic nervous system and the NOTOM escalator concept as one component in the pathogenesis of adolescent idiopathic scoliosis.

There is no generally accepted scientific theory for the causes of adolescent idiopathic scoliosis (AIS). In recent years encouraging advances thought to be related to the pathogenesis of AIS have been made in several fields. After reviewing concepts of AIS pathogenesis we formulated a collective model of pathogenesis. The central concept of this collective model is a normal neuro-osseous timing of maturation (NOTOM) system operating in a child's internal world during growth and maturation; this provides a dynamic physiological balance of postural equilibrium continuously renewed between two synchronous, polarized processes (NOTOM escalator) linked through sensory input and motor output, namely: 1) osseous escalator-increasing skeletal size and relative segmental mass, and 2) neural escalator - including the CNS body schema. The latter is recalibrated continuously as the body adjusts to biomechanical and kinematic changes resulting from skeletal enlargement, enabling it to coordinate motor actions. We suggest that AIS progression results from abnormality of the neural and/or osseous components of these normal escalator in time and/or space - as asynchrony and/or asymmetries - which cause a failure of neural systems to control asymmetric growth of a rapidly enlarging and moving adolescent spine. This putative initiating asymmetric growth in the spine is explained in separate papers as resulting from dysfunction of the hypothalamus expressed through the sympathetic nervous system (leptin-sympathetic nervous system concept for AIS pathogenesis). In girls, the expression of AIS may result from disharmony between the somatic and autonomic nervous systems - relative postural maturational delay in the somatic nervous system and hypothalamic dysfunction in the autonomic nervous system, with the conflict being fought out in the spine and trunk of the girl and compounded by biomechanical spinal growth modulation.

Relative shortening and functional tethering of spinal cord in adolescent scoliosis - Result of asynchronous neuro-osseous growth, summary of an electronic focus group debate of the IBSE.

There is no generally accepted scientific theory for the causes of adolescent idiopathic scoliosis (AIS). As part of its mission to widen understanding of scoliosis etiology, the International Federated Body on Scoliosis Etiology (IBSE) introduced the electronic focus group (EFG) as a means of increasing debate on knowledge of important topics. This has been designated as an on-line Delphi discussion. The Statement for this debate was written by Dr WCW Chu and colleagues who examine the spinal cord to vertebral growth interaction during adolescence in scoliosis. Using the multi-planar reconstruction technique of magnetic resonance imaging they investigated the relative length of spinal cord to vertebral column including ratios in 28 girls with AIS (mainly thoracic or double major curves) and 14 age-matched normal girls. Also evaluated were cerebellar tonsillar position, somatosensory evoked potentials (SSEPs), and clinical neurological examination. In severe AIS compared with normal controls, the vertebral column is significantly longer without detectable spinal cord lengthening. They speculate that anterior spinal column overgrowth relative to a normal length spinal cord exerts a stretching tethering force between the two ends, cranially and caudally leading to the initiation and progression of thoracic AIS. They support and develop the Roth-Porter concept of uncoupled neuro-osseous growth in the pathogenesis of AIS which now they prefer to term 'asynchronous neuro-osseous growth'. Morphological evidence about the curve apex suggests that the spinal cord is also affected, and a 'double pathology' is suggested. AIS is viewed as a disorder with a wide spectrum and a common neuroanatomical abnormality namely, a spinal cord of normal length but short relative to an abnormally lengthened anterior vertebral column. Neuroanatomical changes and/or abnormal neural function may be expressed only in severe cases. This asynchronous neuro-osseous growth concept is regarded as one component of a larger concept. The other component relates to the brain and cranium of AIS subjects because abnormalities have been found in brain (infratentorial and supratentorial) and skull (vault and base). The possible relevance of systemic melatonin-signaling pathway dysfunction, platelet calmodulin levels and putative vertebral vascular biology to the asynchronous neuro-osseous growth concept is discussed. A biomechanical model to test the spinal component of the concept is in hand. There is no published research on the biomechanical properties of the spinal cord for scoliosis specimens. Such research on normal spinal cords includes movements (kinematics), stress-strain responses to uniaxial loading, and anterior forces created by the stretched cord in forward flexion that may alter sagittal spinal shape during adolescent growth. The asynchronous neuro-osseous growth concept for the spine evokes controversy. Dr Chu and colleagues respond to five other concepts of pathogenesis for AIS and suggest that relative anterior spinal overgrowth and biomechanical growth modulation may also contribute to AIS pathogenesis.

Récents progrès dans l’étiopathogénie de la scoliose idiopathique de l’adolescent et nouveaux concepts moléculaires

Adolescent idiopathic scoliosis (AIS) is the most common form of scoliosis that affects a significant number of young teenagers, mainly females (0.2-6 % of the population). Historically, several hypothesis were postulated to explain the aetiology of AIS, including genetic factors, biochemical factors, mechanics, neurological, muscular factors and hormonal factors. The neuroendocrine hypothesis involving a melatonin deficiency as the source for AIS has generated great interest. This hypothesis stems from the fact that experimental pinealectomy in chicken, and more recently in rats maintained in a bipedal mode, produces a scoliosis. The biological relevance of melatonin in idiopathic scoliosis is controversial since no significant decrease in circulating melatonin level has been observed in a majority of studies. Analysis of melatonin signal transduction in musculoskeletal tissues of AIS patients demonstrated for the first time a defect occurring in a cell autonomous manner in different cell types isolated from AIS patients suffering of the most severe form of that disease. These results have led to a classification of AIS patients in three different functional groups depending on their response to melatonin, suggesting that the cause of AIS involves several genes. Molecular analysis showed that melatonin signaling dysfunction is triggered by an increased phosphorylation of Gi proteins inactivating their function. This discovery has led to development of a first scoliosis screening assay. This test, using blood sample, is currently in clinical validation process in Canada and could be used for screening children at high risk of developing AIS.

Molecular Determinants of Melatonin Signaling Dysfunction in Adolescent Idiopathic Scoliosis

Presently, the genetic cause of adolescent idiopathic scoliosis (AIS), the most common form of scoliosis, remains unclear. Among many hypotheses, the neuroendocrine hypothesis involving a melatonin deficiency as the source for AIS generated the greatest interest and controversy since no decrease in circulating melatonin level has been observed in a majority of studies. Previously, we have reconciled the role of melatonin in AIS by demonstrating a melatonin signaling dysfunction occurring in osteoblasts derived from AIS patients, which contrasted with similar cells isolated from healthy subjects. We found that this difference is caused in AIS cells by increased phosphorylation of serine residues affecting the activity of G inhibitory proteins normally associated with melatonin cell surface receptors. Here we propose a preliminary molecular classification of patients with AIS based on the cellular response to the melatonin (cAMP) and distinct protein-protein interactions. These interactions include those between protein kinase C delta (PKCdelta) and MT2 melatonin receptors or PKCdelta and the receptor for activated protein C kinase 1. This finding could help in future molecular classification of patients with AIS.

Biomechanical spinal growth modulation and progressive adolescent scoliosis--a test of the 'vicious cycle' pathogenetic hypothesis: summary of an electronic focus group debate of the IBSE.

There is no generally accepted scientific theory for the causes of adolescent idiopathic scoliosis (AIS). As part of its mission to widen understanding of scoliosis etiology, the International Federated Body on Scoliosis Etiology (IBSE) introduced the electronic focus group (EFG) as a means of increasing debate on knowledge of important topics. This has been designated as an on-line Delphi discussion. The text for this debate was written by Dr Ian A Stokes. It evaluates the hypothesis that in progressive scoliosis vertebral body wedging during adolescent growth results from asymmetric muscular loading in a "vicious cycle" (vicious cycle hypothesis of pathogenesis) by affecting vertebral body growth plates (endplate physes). A frontal plane mathematical simulation tested whether the calculated loading asymmetry created by muscles in a scoliotic spine could explain the observed rate of scoliosis increase by measuring the vertebral growth modulation by altered compression. The model deals only with vertebral (not disc) wedging. It assumes that a pre-existing scoliosis curve initiates the mechanically-modulated alteration of vertebral body growth that in turn causes worsening of the scoliosis, while everything else is anatomically and physiologically 'normal' The results provide quantitative data consistent with the vicious cycle hypothesis. Dr Stokes' biomechanical research engenders controversy. A new speculative concept is proposed of vertebral symphyseal dysplasia with implications for Dr Stokes' research and the etiology of AIS. What is not controversial is the need to test this hypothesis using additional factors in his current model and in three-dimensional quantitative models that incorporate intervertebral discs and simulate thoracic as well as lumbar scoliosis. The growth modulation process in the vertebral body can be viewed as one type of the biologic phenomenon of mechanotransduction. In certain connective tissues this involves the effects of mechanical strain on chondrocytic metabolism a possible target for novel therapeutic intervention.

Pedicle growth asymmetry as a cause of adolescent idiopathic scoliosis: a biomechanical study.

Over the last century the neurocentral junction (NCJ) has been identified as a potential cause of adolescent idiopathic scoliosis (AIS). Disparate growth at this site has been thought to lead to pedicle asymmetry, which then causes vertebral rotation and ultimately, the development of scoliotic curves. The objectives of this study are (1) to incorporate pedicle growth and growth modulation into an existing finite element model of the thoracic and lumbar spine already integrating vertebral body growth and growth modulation; (2) to use the model to investigate whether pedicle asymmetry, either alone or combined with other deformations, could be involved in scoliosis pathomechanisms. The model was personalized to the geometry of a nonpathological subject and used as the reference spinal configuration. Asymmetry of pedicle geometry (i.e. initial length) and asymmetry of the pedicle growth rate alone or in combination with other AIS potential pathogenesis (anterior, lateral, or rotational displacement of apical vertebra) were simulated over a period of 24 months. The Cobb angle and local scoliotic descriptors (wedging angle, axial rotation) were assessed at each monthly growth cycle. Simulations with asymmetrical pedicle geometry did not produce significant scoliosis, vertebral rotation, or wedging. Simulations with asymmetry of pedicle growth rate did not cause scoliosis independently and did not amplify the scoliotic deformity caused by other deformations tested in the previous model. The results of this model do not support the hypothesis that asymmetrical NCJ growth is a cause of AIS. This concurs with recent animal experiments in which NCJ growth was unilaterally restricted and no scoliosis, vertebral wedging, or rotation was noted.

Evaluating MRI as a Technique for Visualizing the Neurocentral Junction

Magnetic resonance imaging (MRI) of the neurocentral junction (NCJ) was correlated with gross anatomic and histologic sections acquired at the same position. To determine the composition of the MRI of the NCJ and to explore the long-standing discrepancy between the ages of closure of the NCJ as determined by anatomic and imaging studies. Disparate growth at the site of the NCJ has been implicated as a potential cause of adolescent idiopathic scoliosis since the early 1900s. Although anatomic studies have refuted this theory by maintaining that the NCJ closes before the age of 10 years, recent MRI studies have suggested that the NCJ remains open until adolescence. One hundred fourteen porcine NCJs in various stages of development were visualized using MRI. Gross anatomic and histologic sections were acquired at the same position as MRI for correlation. The presence or absence of NCJ cartilage was represented by the presence or absence of a line on MRI. However, the NCJ image overestimated the width of the NCJ cartilage in the anteroposterior direction during development. As the NCJ underwent the process of closure, the NCJ image underestimated the extent of closure in the medial-lateral direction. Although MRI underestimated the extent of NCJ closure, MRI accurately showed whether cartilage was present or absent at the NCJ site. MRI determination of the age of NCJ closure appears reliable, and further exploration of the asymmetric growth hypothesis is required.

MRI characteristics of the neurocentral synchondrosis.

The neurocentral synchondrosis (NCS) is a cartilaginous growth plate that since the early 1900s has been implicated as a potential cause of adolescent idiopathic scoliosis (AIS). Previous studies have focused only on the closure age without characterizing normal NCS development. Using MRI, the normal development of the NCS image can be characterized, and the stages preceding the disappearance of this image can be specified. A total of 405 NCSs were visualized in 11 normal pediatric patients using T1 and T2 transverse and sagittal MRI views. The images were correlated and the variety of images recorded to categorize the NCS into developmental stages. The development of the NCS was categorized into five developmental stages. The image of the NCS became absent in a specific pattern along the vertebral column, first in the cervical region (age 6), then in the lumbar region (age 12), and finally in the thoracic region (age 14). The normal development of the NCS at the level of individual vertebrae and also along the vertebral column as a whole was determined using MRI. These patterns of development are valuable and necessary to evaluate the role of the NCS in pathological conditions.

Scoliose idiopathique de l'adolescence : la mélatonine est-elle en cause ?

Background. Although the cause of adolescent idiopathic scoliosis remains unclear, pinealectomy is followed by the development of scoliosis in chickens. Melatonin is the only hormone secreted by pineal gland. Objective. To assess serum melatonin levels in adolescents with idiopathic scoliosis. Methods. Serum melatonin was assayed once, at 12:00 AM, in each of 20 adolescents with idiopathic scoliosis and 10 age-matched siblings. In the patient group, mean age was 14.3 years and the mean Cobb angle was 54.5° (range 20°–110°). Mean age in the control group was 14 years. Results. Serum melatonin was significantly lower in the patients (mean, 7.7 pg/mL; range, 4 to 13 pg/mL) than in the controls (mean, 29.9 pg/mL; range, 19.3 to 46 pg/mL) ( P<0.00001). The 12 surgically treated patients had a mean melatonin level of 8.1 pg/ml, versus 7.2 pg/mL in the eight other patients (nonsignificant P and regression coefficient values). Serum melatonin was not significantly correlated with the Cobb's angle (regression coefficient, 0.18; P<0.44). Conclusion. Our data suggest that serum melatonin levels may contribute to the pathogenesis of idiopathic scoliosis.

Magnetic Resonance Imaging of the Brain Stem in Adolescent Idiopathic Scoliosis

The cause of adolescent idiopathic scoliosis remains an enigma. Several studies have demonstrated abnormalities of posture, proprioception, and equilibrium control in patients with adolescent idiopathic scoliosis. These functions are integrated by structures in and around the brain stem. Twenty-seven patients with adolescent idiopathic scoliosis were studied with magnetic resonance imaging to delineate the anatomy of the brain stem in such patients. Imaging was conducted from the hypothalamus to the spinal cord at C3 in 26 patients; the remaining patient underwent an incomplete study because of a claustrophobic reaction. The study group consisted of 25 females and 2 males with an average age of 16 + 5 years. There were 19 right thoracic curves, 5 thoracolumbar curves, and 3 left lumbar curves. The mean primary curve size was 27 degrees at the most recent clinical evaluation. Seven patients were treated with observation, 14 with bracing, and 6 with surgery. The magnetic resonance imaging studies were read independently by three attending radiologists in a randomized, blinded fashion along with the magnetic resonance imaging studies of 11 controls. Asymmetry in the ventral pons or medulla in the area of the corticospinal tracts was noted in seven study patients and one control; one study patient had an enlarged cisterna magna and one an inconclusive (incomplete) study. These findings may support previous studies that have suggested a central nervous system abnormality as a cause of adolescent idiopathic scoliosis.